PROCESS FOR THE PREPARATION OF MORPHINE ANALOGS VIA METAL CATALYZED N-DEMETHYLATION/FUNCTIONALIZATION AND INTRAMOLECULAR GROUP TRANSFER

摘要

The present application is directed to an efficient conversion of C-14 hydroxylated morphine alkaloids to various morphine analogs, such as naltrexone, naloxone and nalbuphone. One feature of this process is an intramolecular functional group transfer from the C-14 hydroxyl to the N-17 nitrogen atom following a palladium-catalyzed N-demethylation.

主权项

1. A process for the preparation of a compound of Formula I: comprising: (a) reacting a compound of Formula II with a compound of Formula IIIa or IIIb under conditions to provide a compound of Formula IV: (b) reacting the compound of Formula IV with a metal catalyst in the presence of an oxidant under conditions to provide a compound of Formula V: (c) treating the compound of Formula V with a reducing agent under conditions to provide the compound of Formula I, wherein each R1 is selected from C3-10cycloalkyl, C1-10alkyl and C6-10aryl, and each LG is a leaving group; wherein in the compounds of the Formulae I, III, IV and V, one or more available hydrogens in R1 is/are optionally replaced with F and/or one or more of available atoms in R1 is/are optionally replaced with an isotopic label.